Persistent Lower Limb Deformities Despite Amelioration of Rickets in X-Linked Hypophosphatemia (XLH) - A Prospective Observational Study

Abstract

Background: Gait deviations, lower limb pain and joint stiffness represent key symptoms in patients with X-linked hypophosphatemia (XLH, OMIM 307800), a rare disorder of mineral homeostasis. While the pathomechanism for rickets is well understood, the direct role of PHEX (Phosphate-regulating neutral endopeptidase) deficiency in non-rachitic features including complex deformities, skull and dental affections remains unclear. FGF23-inhibiting antibody treatment can normalize serum phosphate levels and to improve rickets in XLH patients. However, linear growth remains impaired and effects on lower limb deformity and gait are insufficiently studied.

Aims: To characterize and evaluate the course of lower limb deformity in a case series of pediatric XLH patients receiving Burosumab therapy.

Methods: Comparative assessment of planar radiographs, gait analysis, biochemical and clinical features of pediatric patients before and ≥12 months after initiation of FGF23-inhibiting was performed prospectively. Lower limb maltorsion was quantified by torsional MRI and gait analysis. Standardized deformity analysis of lower limb anteroposterior radiographs was conducted.

Results: Seven patients (age 9.0 +/-3.6 years) were eligible for this study. All patients received conventional treatment before onset of antibody treatment. Maltorsion of the femur was observed in 8/14 legs using torsional MRI (mean antetorsion 8.79°). Maltorsion of the tibia was observed in 9/14 legs (mean external torsion 2.8°). Gait analysis confirmed MRI findings with femoral external malrotation prior to and one year after onset of Burosumab therapy. Internal foot progression (intoeing gait) remained pathological in all cases (mean 2.2°). Knee rotation was pathologically internal 10/14 legs. Mean mechanical axis deviation (MAD) of 16.1mm prior to Burosumab changed in average by 3.9mm. Three children underwent guided growth procedures within the observation period. Mild postprocedural rebound of frontal axis deviation was observed under Burosumab treatment in one patient.

Conclusions: This is the first study to investigate lower limb deformity parameters quantitatively in children with XLH receiving Burosumab. One year of Burosumab therapy was associated with persistent maltorsion and frontal axis deviation (varus/valgus) despite improved rickets in this small, prospective uncontrolled study.

Keywords: Burosumab; FGF23.; X-linked hypophosphatemia (XLH); deformities; phosphate; skeletal dysplasia; torsion.

Figure 1

Box plot chart of biochemical, radiographic, and anthropometric markers of treatment response in XLH under conventional treatment (orange) and one year after switch to Burosumab treatment (green). Boxes show median values, upper and lower quartiles.

Figure 2

Gait cycle analysis showing overall external hip rotation of children with XLH (n=14 legs) prior to Burosumab (red line) and 12 months after start of Burosumab (blue line) compared to a pediatric control group (gray area) (A). Internal knee rotation (B) and internal foot progression (C) was observed. Mean value and one standard deviation (dashed line) are presented. Control group band is presented as +/-one standard deviation.

Figure 3

Box chart comparison of gait analysis data (mean rotation during stance) under conventional treatment (orange) and one year after switch to Burosumab treatment (green). X-axis indicates degrees, boxes show median values, upper and lower quartiles. Negative values represent external rotation, positive values internal rotation. Blue boxes represent reference ranges of healthy pediatric controls (Adapted from Servier Medical Art by Servier under a Creative Commons Attribution 3.0 Unported License).

Figure 4

(A) Femoral torsion (MRI measurement) observed in the XLH cohort (yellow dots represent each femur) with Burosumab therapy compared to the norm group (grey). 8/14 femora showed reduced antetorsion, respectively retrotorsion. Radiographic norm group values (+-1SD) were obtained from Fabry et al. (17). (B) Tibial torsion (MRI) was assessed in a XLH population undergoing Burosumab therapy (yellow dots represent each tibia). 9/14 legs showed reduced external tibial torsion. Clinical reference values (+-2SD) obtained by Staheli et al. (18) are shown by the grey area.

Figure 5

Case 2: Radiographs (A-C) and torsional MRI (D) of a 10-year-old girl undergoing Burosumab therapy. Full long leg standing radiographs were obtained prior (A) to Burosumab initiation and during treatment. Lateralization of MAD in one leg was observed at the 10-month follow-up (B). Guided growth procedure using temporary hemiepiphysiodesis was performed on the right tibia with short term success 6 months postoperative (plate not yet removed) (C). Torsional MRI showed 2° internal torsion of the femur and 3° external torsion of the tibia (D).

Figure 6

Wrist and knee radiographs obtained before therapy onset (A, C) and at the one-year follow-up show resolution of rickets (B, D) in case 2. Linear growth, onset of treatment and thelarche (B2) are marked on the Austrian reference growth chart for girls (E). The course of relevant biochemical parameters shows increase of serum Phosphate and normalization of ALP with onset of Burosumab treatment around 10 years of age (F).

Figure 7

Lower limb deformity in a 7-year-old girl (case 3) undergoing Burosumab therapy. Full long leg standing radiographs and lower limb deformity analysis were obtained prior (A) to initiation, as well as during follow-up appointments. Valgus deformity was observed and a temporary hemiepiphysiodesis procedure performed in both legs (x-ray 2 months postoperative) despite persistent rachitic status (B). Normalization of MAD in one leg occurred sooner (C). As a sign of valgus deformity rebound, a mild recurrence of lateralization of the MAD after successful guided growth surgery despite Burosumab therapy was observed at the last follow-up 12 months after plate removal (D).

Figure 8

Radiographic progress of lower limb deformity in a 9 years 11 months old girl with familial XLH (case 6). Guided growth surgery was performed at age 5 years 1 month for varus deformity many years before Burosumab therapy (A). Mechanical axis remained stable during follow-up before initiation of treatment (B), at the one-year follow-up (C), as well as the last follow-up 6.5 years after guided growth (D).

Figure 9

Wrist and knee radiographs obtained before therapy onset (A, C) and at the one-year follow-up show resolution of rickets (B, D) in case 6. Linear growth, onset of treatment and thelarche (B2) are marked on the Austrian reference growth chart for girls (E). The course of relevant biochemical parameters shows increase of serum phosphate and normalization of ALP with onset of Burosumab treatment around 10 years of age (F).